Triazole compounds and the use thereof

ABSTRACT

The present invention relates to triazole compounds of the following formula:                    
     where R 1 , R 2 , A, B and Ar have the meanings stated in the description. The compounds according to the invention have a high affinity for the dopamine D 3  receptor and can therefore be used to treat disorders which respond to dopamine D 3  ligands.

This application is a divisional application of U.S. application Ser. No. 08/765,916 (allowed), filed Jan. 14, 1997, under 35 U.S.C. §371 as a national stage application of Internation Application No. PCT/EP 95/02,781, which was filed Jul. 14, 1995.

The invention relates to triazole compounds and to the use of such compounds. Said compounds have valuable therapeutic properties and can be used to treat disorders which respond to dopamine D₃ receptor ligands,

Compounds which are of the type under discussion here and have physiological activity have been disclosed. U.S. Pat. Nos. 4,338,453, 4,408,049 and 4,577,020 describe triazole compounds which have antiallergic activity.

Neurons receive their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of them is dopamine.

Confirmed findings on the presence of dopamine and its physiological function as neurotransmitter have been published. Cells which respond to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other disorders are treated with drugs which interact with dopamine receptors.

By 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, namely D₁ and D₂ receptors.

Sokoloff et al., Nature 1990, 347: 146-151, found a third subtype, namely D₃ receptors. They are expressed mainly in the limbic system. The D₃ receptors differ structurally from the D₁ and D₂ receptors in about half the amino-acid residues.

The effect of neuroleptics has generally been ascribed to their affinity for D₂ receptors. Recent receptor-binding studies have confirmed this. According to these, most dopamine antagonists, like neuroleptics, have high affinity for D₂ receptors but only low affinity for D₃ receptors.

We have now found, surprisingly, that the compounds according to the invention have a high affinity for the dopamine D₃ receptor and only a low affinity for the D₂ receptor. They are thus selective D₃ ligands.

The present invention therefore relates to triazole compounds of the formula I:

where

A is a straight-chain or branched C₁-C₁₈-alkylene group which may comprise at least one group selected from O, S, NR³, CONR³, NR³CO, COO, OCO, C₃-C₆-cycloalkylene or a double or triple bond,

X is a radical of the formula:

R¹ is H, CO₂R³, NR³R⁴, OR⁴, C₃-C₆-cycloalkyl or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen;

R² has the meanings indicated for R¹ or is CF₃, SR³, halogen or CN;

R³ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl, phenyl or halogen;

R⁴ has the meanings indicated for R³ or is COR³ or CO₂R³;

Ar is phenyl, pyridyl, pyrimidyl or triazine, where AR may have from one to four substituents which are selected, independently of one another, from OR⁴, C₁-C₈-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, CO₂R³, NO₂, SO₂R³, SO₃R³, NR³R⁴, SO₂NR³R⁴, SR³, CF₃, CHF₂, a 5- or 6-membered carbocyclic aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic aromatic or nonaromatic ring having 1 to 4 hetero atoms selected from O, S and N, where the carbocyclic or heterocyclic ring may be unsubstituted or substituted by C₁-C₈-alkyl, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃ and where Ar may also be fused to a carbocyclic or heterocyclic ring of the type defined above, and the salts thereof with physiologically tolerated acids.

The compounds according to the invention are selective dopamine D₃ receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D₂ receptor, have fewer side effects than classical neuroleptics, which are D₂ receptor antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D₃ receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses. They can additionally be used to treat sleep disorders and nausea and as antihistamines.

Within the scope of the present invention, the following terms have the meanings indicated below:

Alkyl (also in radicals such as alkoxy, alkyl-amino etc.) means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of one another, from OH and OC₁-C₈-alkyl.

Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl etc.

Alkylene stands for straight-chain or branched radicals having, preferably, 2 to 15 carbon atoms, particularly preferably 3 to 10 carbon atoms.

The alkylene groups may comprise at least one of the abovementioned groups. This can—just like the double or triple bond mentioned—be arranged in the alkylene chain at any point or at the end of the chain so that it connects the chain to the triazole residue. The latter is preferred. When the alkylene group comprises a double or triple bond, it has at least three carbon atoms in the chain.

Halogen is F, Cl, Br, I and, in particular, Cl, Br, I.

R¹ and R² are preferably, independently of one another, H, C₁-C₈-alkyl, NR³R⁴ or OR⁴.

Ar can have one, two, three or four substituents. They are preferably selected, independently of one another, from halogen, CF₃, CHF₂, NR³R⁴, OR⁴, NO₂, C₁-C₈-alkyl, OC₁-C₈-alkyl, SR³ and CN, where R³ and R⁴ have the abovementioned meanings.

If one of the substituents of Ar is C₁-C₈-alkyl, a branched radical, in particular the isopropyl or t-butyl group, is preferred.

Ar preferably has at least one substituent and is, in particular,

where D¹, D² and D³ are, independently of one another, CR or N, and R, X and Y are H or are the substituents of the radical Ar indicated above or below.

Ar is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidyl.

When one of the substituents of the radical Ar is a 5- or 6-membered heterocyclic ring, examples thereof are a pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole or thiadiazole residue.

When one of the substituents of the radical Ar is a carbocyclic radical, it is, in particular, a phenyl, cyclopentyl or cyclohexyl radical.

When Ar is fused to a carbocyclic or heterocyclic radical, Ar is, in particular, a naphthalene, di- or tetrahydronaphthalene, quinoline, di- or tetrahydroquinoline, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole or benzotriazole residue.

X is preferably

A preferred embodiment comprises compounds of the formula I where A is C₃-C₁₀-alkylene which comprises at least one group which is selected from O, S, NR³, cyclohexylene, in particular 1,4-cyxclohexylene, and a double or triple bond, where R³ is as defined above.

Another preferred embodiment comprises compounds of the formula I where

R¹ is H, OR⁴ where R⁴ is H or C₁-C₈-alkyl, or C₃-C₆-cycloalkyl or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen;

R² is H, C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or NR³R⁴ where R³ and R⁴ are, independently of one another, H, phenyl-C₁-C₈-alkyl or C₁-C₈-alkyl, or OR⁴ where R⁴ is H or C₁-C₈-alkyl, or CF₃;

A is as defined in claim 3, and

Ar is phenyl, pyridyl or pyrimidyl which may have one, two, three or four substituents which are selected from H, C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or OR⁴ where R⁴ is H, C₁-C₆-alykl [sic] which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or CHF₂, CF₃, CN, Halogen, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, naphthyl and a 5- or 6-membered heterocyclic aromatic radical with 1 to 3 hetero atoms selected from O, N and S.

Another preferred embodiment comprises compounds of the formula I where

R¹ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen;

R² is H, C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or NR³R⁴ where R³ and R⁴ are, independently of one another, H or C₁-C₈-alkyl, or OR⁴ where R⁴ is H or C₁-C₈-alkyl, or CF₃;

A is C₁-C₁₀-alkylene which may comprise and oxygen or sulfur atom or the group NR³ where R³ is as defined above;

Ar is phenyl which may have one to four substituents which are selected, independently of one another, from H, CN, SR³, halogen, C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or phenyl, naphthyl, OR⁴, NO₂, NR³R⁴, CHF₂ and CF³, where R³ and R⁴ have the stated meanings.

Particularly preferred in this connection are the compounds of the formula I where

A is SC₃-C₁₀-alkylene, OC₃-C₁₀-alkylene or NR³—C₃-C₁₀-alkylene, where R³ is H or C₁-C₈-alkyl,

R¹ is H or C₁-C₈-alkyl;

R² has the abovementioned meanings;

X is

Ar is phenyl which has one to four substituents which are, independently of one another, H, C₁-C₈-alkyl, OC₁-C₈-alkyl, CHF₂, CF₃ or CN.

Ar has, in particular, two substituents which are located in positions 3 and 5, with one substituents being CF₃, CHF₂ or C₁-C₈-alkyl and the other substituent being H or C₁-C₈-alkyl.

Another preferred embodiment comprises compounds of the formula I where

Ar is pyrimidinyl which has one to three substituents which are selected, independently of one another, from H, C₁-C₈-alkyl, phenyl, naphthyl, C₃-C₆-cycloalky, OH, OC₁-C₈-alkyl, halogen, CN, CF₃, CHF₂ and a 5- or 6-membered heterocyclic aromatic radical with 1 to 3 hetero atoms selected from O, N and S;

R¹ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen,

R² is H, NR³R⁴ or OR⁴ where R³ and R⁴ are, independently of one another, H, C₁-C₈-alkyl or phenyl-C₁-C₈-alkyl;

A is C₁-C₁₀-alkylene which may comprise at least one group selected from O, S, NR₃ where R³ is H or C₁-C₈-alkyl, and a double or triple bond; and

X is as defined above.

Another preferred embodiment comprises compounds of the formula I where

Ar is pyridinyl which has one to four substituents which are selected, independently of one another, from H, C₁-C₈-alkyl, phenyl, naphthyl, OH, OC₁-C₈-alkyl, halogen, CF₃, CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl and a 5- or 6-membered heterocyclic aromatic radical with 1 to 3 hetero atoms selected from O, N and S;

R¹ is H, C₁-C₈-alkyl, C₃-C₆-cycloalkyl or OR⁴ where R⁴ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen; and

R², A and X are as defined above.

The invention also embraces the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung, Volume 10, pages 224 et seq., Birkhäuser Verlag, Basle and Stuttgart, 1996.

The compounds of the formula [sic] I may have one or more centers or asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The invention also includes the tautomeric forms in each case.

The compounds of the formula [sic] I can be prepared by methods similar to conventional ones as described, for example, in Houben Weyl “Handbuch der Organischen Chemie”, 4th Ed., Thieme Verlag, Stuttgart 1994, Volume E8/d, pages 479 et seq.; and A. R. Katritzky, C. W. Rees (ed.) “Comprehensive Heterocyclic Chemistry”, 1st Ed. Pergamon Press 1984, in particular Vol. 5, part 4a, pages 733 et seq. and literature cited therein. The process for preparing the compounds comprises

i) reacting a compound of the general formula II:

where Y is a conventional leaving group, with a compound of the general formula III

H—X—Ar

ii) to prepare a compound of the formula I where A is an oxygen or sulfur atom or NR³:

a) reacting a compound of the general formula IV:

where Z¹ is O, S or NR³ and A¹is C₀-C₁₈-alkylene, with a compound of the general formula VI

Y¹—A²—X—Ar

where Y¹ has the abovementiones meanings, and A² is C₁-C₁₈-alkylene, where A¹ and A² together have 1 to 18 carbon atoms;

iii) to prepare a compound of the formula I where A comprises the group COO or CONR³:

a) reacting a compound of the general formula VII:

where Y² is OH, OC₁-C₈-alkyl, Cl or, together with CO, is an activated carboxyl group, and A¹ has the abovementioned meanings, with a compound of the formula VIII:

Z¹—A²—X—Ar

where A² has the abovementioned meanings, and Z¹ is OH or NHR³,

iv) to prepare a compound of the formula I where A comprises the group OCO or NR³CO:

a) reacting a compound of the formula IV

where Z¹ is O or NR³, with a compound of the formula X:

Y²CO—A²—X—Ar

where X and Y² have the abovementioned meanings, and where R¹, R², A, X and Ar have the abovementioned meanings.

The reactions described above generally take place in a solvent at from room temperature to the boiling point of the solvent used. Examples of solvents which can be used are ethyl acetate, tetrahydrofuran, dimethylformamide, dimethoxyethane, toluene, xylene or a ketone, such as acetone or methyl ethyl ketone.

An acid acceptor is present if required. Suitable acid acceptors are inorganic bases such as sodium or potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride or organic bases such as triethylamine or pyridine. The latter may also serve as solvents.

The crude product is isolated in a conventional way, for example by filtration, removal of the solvent by distillation or extraction from the reaction mixture. The resulting compound can be purified in a conventional way, for example by recrystallization from a solvent, chromatography or conversion into an acid addition compound.

The acid addition salts are prepared in a conventional way by mixing the free base with the appropriate acid, possibly in solution in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, an ether such as methyl t-butyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate.

The abovementioned starting materials are disclosed in the literature or can be prepared by known processes.

To treat the abovementioned disorders, the compounds according to the invention are administered in a conventional manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 10 to 1000 mg per patient and day on oral administration and about 1 to 500 mg per patient and day on parenteral administration.

The invention also relates to pharmaceutical compositions which contain the compounds according to the invention. These compositions are in the usual solid or liquid pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. The active substances can in these cases be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmaceutics Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain the active substance in an amount from 1 to 99% by weight.

The following examples serve to explain the invention without limiting it.

EXAMPLE 1 4-Methyl-3-[3-(4-{3-trifluoromethylphenyl}piperazinyl)propylmercapto]-4H-1,2,4-triazole

a) 1-(3-Chloropropyl)-4-(3-trifluoromethylphenyl)piperazine

30 g (0.13 mol) of m-trifluoromethylphenylpiperazine, 23 g (0.146 mol) of 1,3-bromochloropropane [sic ] and 15 g (0.148 mol) of triethylamine in 200 ml of THF were refluxed for 4 hours. Cooling was followed by filtration with suction and concentration. The viscous residue was taken up in ethyl acetate, washed with water, dried over MgSO₄ and then concentrated. The resulting residue comprised 39 g of product as yellowish oil (quantitative yield).

b) 4-Methyl-3-[3-(4-{3-trifluoromethylphenyl}piperazinyl)propylmercapto]-4H-1,2,4-triazole

1.15 g (10 mmol) of 3-mercapto-4-methyl-4H-1,2,4-triazole, 3.1 g (10.1 mmol) of 1-(3-chloropropyl)-4-(3-trifluoromethylphenyl)piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF were stirred at 100° C. for 1 hour. The mixture was then poured into 5% strength hydrochloric acid and extracted with ethyl acetate. The aqueous phase was made alkaline with sodium hydroxide solution and then extracted again with ethyl acetate, and the organic phase was dried over MgSO₄ and concentrated. The residue was purified by chromatography (mobile phase: CH₂Cl₂/CH₃OH=95/5). 2.1 g of product were obtained as a yellowish oil (=55% yield).

H-NMR [δ, ppm]: 2.02 (2H); 2.55 (2H); 2.61 (4H); 3.23 (6H); 3.33 (2H); 3.61 (3H); 7.06 (3H); 7.33 (1H); 8.12 (1H)

EXAMPLE 2 4-Methyl-3-[5-(4-{3-trifluoromethylphenyl}piperazinyl)pentylmercapto]-4H-1,2,4-triazole

a) 3-(5-Chloropentylmercapto)-4-methyl-4H-1,2,4-triazole

2.88 g (25 mmol) of 3-mercapto-4-methyl-4H-1,2,4-triazole, 4.64 g (25 mmol) of 1,5-bromochloropentane [sic] and 5.58 g (25.5 mmol) of triethylamine in 100 ml of THF were refluxed for 4 hours. Cooling was followed by filtration with suction, concentration and purification of the residue by chromatography (mobile phase: CH₂Cl₂/CH₃OH=95/5). 1.9 g of product were obtained (=35% yield).

b) 4-Methyl-3-[5-(4-{3-trifluoromethylphenyl}piperazinyl)pentylmercapto]-4H-1,2,4-triazole

1.9 g (8.66 mmol) of product from 2a), 2.19 g (9.52 mmol) of m-trifluoromethylphenylpiperazine and 0.96 g (9.52 mmol) of triethylamine in 5 ml of DMF were stirred at 90° C. for 5 hours. The mixture was then poured into water and extracted three times with CH₂Cl₂, and the organic phase was dried over MgSO₄ and concentrated. The residue was mixed with methyl t-butyl ether and filtered with suction, and the mother liquor was concentrated. Purification by chromatography (mobile phase: CH₂Cl₂/CH₃OH=95/5) resulted in 2.1 g of product (=59% yield). Melting point 70-76° C.

The following compounds were prepared in a similar way:

Physical data, H-NMR [δ, ppm] No. Example melting point [° C.] 3

1.83(2H); 2.45(6H); 3.0(2H); 3.27(4H); 6.0(2H); 7.05(1H); 7.15(1H); 7.2(1H); 7.4(1H); 11.95(1H) 4

1.85(2H); 2.3(3H); 2.45(2H); 2.5(4H); 3.1(2H); 3.2(4H); 5.8(2H); 7.05(1H); 7.15(1H); 7.2(1H); 7.41(1H) 5

2.1(2H); 2.7(6H); 3.22(2H); 3.42(4H); 7.1(3H); 7.38(1H); 7.92(1H) 6

200-205 7

2.05(2H); 2.55(2H); 2.6(4H); 3.23(4H); 3.4(2H); 3.65(3H); 7.08(3H); 7.35(1H) 8

2.0(2H); 2.53(2H); 2.6(4H); 3.13(2H); 3.25(7H); 7.08(3H); 7.35(1H); 9.88(1H) 9

1.5(6H); 1.98(2H); 2.55(2H); 2.62(4H); 3.15(2H); 3.22(4H); 4.32(1H); 7.08(3H); 7.35(1H); 10.0(1H) 10 

1.95(2H); 2.5(2H); 2.58(4H); 3.1(2H); 3.22(4H); 3.4(3H); 4.4(2H); 7.08(3H); 7.35(1H) 11 

2.52(4H); 3.0(2H); 3.22(4H); 3.4(3H); 3.64(2H); 4.96(2H); 5.62(1H); 5.72(1H); 7.05(3H); 7.3(1H) 12 

1.95(2H); 2.52(2H); 2.6(4H); 3.12(2H); 3.22(4H); 3.4(3H); 4.2(2H); 6.6(1H); 7.0(3H); 7.35(1H) 13 

1.15(6H); 1.75(2H); 2.45(10H); 2.9(2H); 3.08(4H); 3.3(3H); 5.95(2H); 6.45(1H); 6.55(2H) 14 

166-171 15 

1.25(18H); 1.75(2H); 2.4(2H); 2.45(4H); 2.9(2H); 3.1(4H); 3.35(3H); 5.95(2H); 6.75(2H); 6.88(1H)

The compounds according to the invention which are compiled in Tables 1 to 3 below were obtained in a similar manner.

The compounds compiled in Tables 4 to 8 below can likewise be obtained in a similar manner.

TABLE 1

Example No. R¹ R² R⁶ X—Y A¹ A² 16 CH₃ NH₂ i Prop CH₂—N S —(CH₂)₃— 17 CH₃ NH₂ CF₃ CH₂—N S —(CH₂)₂CH═CH(CH₂)₂— 18 CH₃ NH₂ CF₃ CH₂—N S —(CH₂)₂— 19 CH₃ NH₂ CF₃ CH₂—N S —CH₂C(CH₃)═CHCH₂— 20 CH₃CH₂ NH₂ CF₃ CH₂—N S —(CH₂)₃— 21 CH₃ NH₂ CF₃ CH₂—N S

22 n Prop NH₂ CF₃ CH₂—N S —(CH₂)₃— 23 i Prop NH₂ CF₃ CH₂—N S —(CH₂)₃— 24 CH₃CH₂ NH₂ CHF₂ CH₂—N S —(CH₂)₃— 25 n Prop NH₂ CHF₂ CH₂—N S —(CH₂)₃— 26 CH₃CH₂ NH₂ i Prop CH₂—N S —(CH₂)₃— 27 n Prop NH₂ i Prop CH₂—N S —(CH₂)₃— 28 i Prop NH₂ i Prop CH₂—N S —(CH₂)₃— 29 CH₃ NH₂ CF₃ CH₂—N S —(CH₂)₇— 30 CH₃ NH₂ CF₃ CH₂—N S —(CH₂)₈— 31 CH₃ NH₂ i Prop CH₂—N S —(CH₂)₉ 32 CH₃ NH₂ CF₃ CH₂—N S —(CH₂)₄O(CH₂)₄— 33 CH₃ NH₂ i Prop CH₂—N S —(CH₂)₄O(CH₂)₄— 34 CH₃ NHCH₃ CF₃ CH₂—N S —(CH₂)₃— 35 CH₃ NH₂ i Prop CH₂—N S —CH₂C(CH₃)═CHCH₂— 36 CH₃ NH₂ CF₃ CH═N S —(CH₂)₃— 37 CH₃ NHCH₃ CHF₂ CH₂—N S —(CH₂)₃—

TABLE 2

Example No. R¹ R² R⁶ D R⁸ X—Y A B 38 CH₃ NH₂ CF₃ CH H CH₂—N S —(CH₂)₃— 39 CH₃ NH₂ Cl CH CF₃ CH₂—N S —(CH₂)₃— 40 CH₃ NH₂ t But N CF₃ CH₂—N S —(CH₂)₃— 41 CH₃ NH₂ 1-Pyrrolyl N CH₃ CH₂—N S —(CH₂)₃— 42 CH₃ NH₂ t But N CF₃ CH₂—N S —CH₂C(CH₃)═CHCH₂— 43 CH₃ NH₂ t But N CF₃ CH₂—N S —(CH₂)₃— 44 CH₃ NH₂ t but N t But CH₂—N S —(CH₂)₃— 45 CH₃ NH₂ i Prop C—CN i Prop CH₂—N S —(CH₂)₃—

TABLE 3 Physical data of the compounds of Examples 16-45 Example No. Mp. ° C. ¹H—NMR 16 1.2 (6H); 1.9 (2H); 2.5 (6H); 2.8 (1H); 3.2 (6H); 3.5 (3H); 4.4 (2H); 6.7 (3H); 7.1 (1H) 17 194-196° Dihydrochloride 18 109-110° Hydrochloride 19 132-134° 20 1.3 (3H); 2.0 (2H); 2.5 (6H); 3.2 (6H); 3.8 (2H; 4.6 (2H); 7.0 (3H); 7.4 (1H) 21 154-155° 22 1.0 (3H); 1.8 (2H); 2.0 (2H); 2.5 (6H); 3.1 (6H); 3.7 (2H); 4.4 (2H); 7.0 (3H); 7.3 (1H) 23 1.2 (6H); 2.0 (2H); 2.3 (6H); 3.1 (6H); 4.1 (2H); 4.3 (1H); 7.0 (3H); 7.2 (1H) 24 1.2 (3H); 1.8 (2H); 2.4 (2H) 2.5 (4H); 2.9 (2H); 3.1 (4H); 3.8 (2H); 6.0 (2H); 6.9 (1H); 7.0 (3H), 7.3 (1H) 25 1.0 (3H); 1.7 (2H); 2.0 (2H); 2.5 (2H); 2.6 (4H); 3.0 (6H), 3.7 (2H), 4.6 (2H); 6.6 (1H); 7.0 (3H); 7.4 (1H) 26 1.2 (9H); 1.9 (2H); 2.5 (2H); 2.6 (4H); 2.9 (1H); 3.15 (6H); 3.8 (2H); 6.8 (3H); 7.2 (1H) 27 0.9 (3H); 1.2 (6H), 1.7 (2H); 1.9 (2H); 2.5 (2H); 2.6 (4H); 2.8 (1H); 2.9 (2H); 3.2 (4H); 3.4 (2H); 6.8 (3H); 7.3 (1H) 28 1.2 (6H); 1.5 (6H); 1.9 (2H); 2.4 (2H); 2.5 (4H); 2.8 (1H); 3.2 (6H), 4.3 (3H); 6.75 (3H), 7.15 (1H) 29 118-119° 30 164-166° Fumarate 31 1.2 (6H); 1.4 (14H), 1.7 (2H); 2.4 (2H), 2.6 (4H), 2.8 (1H); 3.0 (2H); 3.2 (4H), 3.4 (3H), 4.6 (2H), 6.8 (3H); 7.2 (1H) 32 1.7 (8H); 2.4 (2H); 2.6 (4H); 3.0 (2H; 3.3 (4H); 3.5 (7H); 4.8 (2H); 7.1 (3H); 7.3 (1H) 33 1.2 (6H); 1.6 (8H); 2.4. (2H); K 2.6 (4H); 2.9 (1H); 3.1 (2H); 3.2 (4H); 3.3 (7H); 4.8 (2H); 6.8 (3H); 7.2 (1H) 34 234-270° Trihydrochloride 35 126-129° 36  93-100° 37 234-235° Dihydrochloride 38 153-155° 39 116-118° 40 51-60° 41 65-67° 42 67-72° 43 121-126° 44 180-183° Fumarate 45 130-133°

TABLE 4

Example No. R1 R2 R5 R6 R7 R8 R9 X—Y A¹ A² 46 CH₃ NH₂ H tBut H Me H CH₂—N S —(CH₂)₃— 47 CH₃ NH₂ H tBut H Ph H CH₂—N S —(CH₂)₃— 48 CH₃ NH₂ H tBut H 1-Pyrrolyl H CH₂—N NH —(CH₂)₃— 49 CH₃ NH₂ H iProp H 2-Napht H CH═C —CH₂— —(CH₂)₃— 50 CH₃ NH₂ H Et H tBut H CH₂—N S —(CH₂)₃— 51 CH₃ NH₂ OMe tBut H H H CH═C —CH₂— —(CH₂)₃— 52 CH₃ NH₂ OMe CF₃ H H H CH═C S —(CH₂)₃— 53 CH₃ NH₂ H CF₃ H tBut H CH₂—N NH —(CH₂)₃— 54 CH₃ NH₂ OiProp iProp H H H CH₂—N S —(CH₂)₃— 55 CH₃ NH₂ H H CN tBut H CH₂—N O —(CH₂)₃— 56 CH₃ NH₂ H H F tBut H CH═C S —(CH₂)₃— 57 CH₃ NH₂ H H Cl iProp H CH₂—N —CH₂— —(CH₂)₃— 58 CH₃ NH₂ H tBut H H OMe CH₂—N S —(CH₂)₃— 59 CH₃ NH₂ OMe tBut H tBut H CH₂—N S —(CH₂)₃— 60 CH₃ NH₂ OMe tBut H CF₃ H CH₂—N S —(CH₂)₃— 61 CH₃ NH₂ OMe CF₃ H tBut H CH₂—N NH —(CH₂)₃— 62 CH₃ NH₂ H nProp CN tBut H CH═C —CH₂— —(CH₂)₃— 63 CH₃ NH₂ H CF₃ CN iProp H CH₂—N S —(CH₂)₃— 64 CH₃ NH₂ H Ph C≡CH tBut H CH═C —CH₂— —(CH₂)₃— 65 CH₃ NH₂ OMe tBut CN H H CH═C S —(CH₂)₃— 66 CH₃ NH₂ H tBut CN CF₃ OMe CH₂—N NH —(CH₂)₃— 67 CH₃ NH₂ OMe nProp F tBut H CH₂—N S —(CH₂)₃— 68 CH₃ NH₂ H Ph CN tBut Me CH₂—N O —(CH₂)₃— 69 CH₃ NH₂ OMe tBut F H H CH═C S —(CH₂)₃— 70 CH₃ NH₂ H iProp H H OMe CH₂—N S —(CH₂)₃— 71 iProp NH₂ H tBut H Me H CH₂—N S —(CH₂)₃— 72 iProp NH₂ H tBut H Ph H CH₂—N NH —(CH₂)₄— 73 iProp NH₂ H tBut H 1-Pyrrolyl H CH₂—N S —(CH₂)₄— 74 iProp NH₂ H iProp H 2-Napht H CH₂—N —CH₂— —(CH₂)₃— 75 iProp NH₂ H Et H tBut H CH₂—N S —(CH₂)₅— 76 iProp NH₂ OMe tBut H H H CH₂—N O —(CH₂)₅— 77 iProp NH₂ OMe CF₃ H H H CH═C NH —(CH₂)₄— 78 iProp NH₂ H CF₃ H tBut H CH₂—N —CH₂— —(CH₂)₄— 79 iProp NH₂ OiProp iProp H H H CH═C S —(CH₂)₃— 80 iProp NH₂ H H CN tBut H CH₂—N NH —(CH₂)₃— 81 iProp NH₂ H H F tBut H CH₂—N S —(CH₂)₃— 82 iProp NH₂ H H Cl iProp H CH═C —CH₂— —(CH₂)₃— 83 iProp NH₂ H tBut H H OMe CH₂—N S —(CH₂)₃— 84 iProp NH₂ OMe tBut H tBut H CH₂—N S —(CH₂)₄— 85 iProp NH₂ OMe tBut H CF₃ H CH₂—N S —(CH₂)₃— 86 iProp NH₂ OMe CF₃ H tBut H CH₂—N NH —(CH₂)₅— 87 iProp NH₂ H nProp CN tBut H CH═C —CH₂— —(CH₂)₃— 88 iProp NH₂ H CF₃ CN iProp H CH₂—N S —(CH₂)₄— 89 iProp NH₂ H Ph C═CH tBut H CH═C —CH₂— —(CH₂)₃— 90 iProp NH₂ OMe tBut CN H H CH═C S —(CH₂)₆— 91 iProp NH₂ H tBut CN CF₃ OMe CH₂—N NH —(CH₂)₃— 92 iProp NH₂ OMe nProp F tBut H CH₂—N S —(CH₂)₅— 93 iProp NH₂ H Ph CN tBut Me CH₂—N O —(CH₂)₃— 94 iProp NH₂ OMe tBut F H H CH═C S —(CH₂)₄— 95 iProp NH₂ H iProp H H OMe CH₂—N S —(CH₂)₃— 96 iProp NHMe H tBut H Me H CH₂—N S —CH₂—CH═CH—CH₂— 97 iProp NHMe H tBut H Ph H CH₂—N —CH₂— —CH₂—CH═CH—CH₂— 98 iProp NHMe H tBut H 1-Pyrrolyl H CH₂—N S —CH₂—CH═CH—CH₂— 99 iProp NHMe H iProp H 2-Napht H CH₂—N NH —CH₂—C(CH₃)═CH—CH₂— 100  iProp NHMe H Et H tBut H CH₂—N S —CH₂—C(CH₃)═CH—CH₂— 101  iProp OH OMe tBut H H H CH₂—N —CH₂— —CH₂—C(CH₃)═CH—CH₂— 102  iProp OH OMe CF₃ H H H CH₂—N NH —CH₂—C(CH₃)═CH—CH₂— 103  iProp OH H CF₃ H tBut H CH₂—N S —CH₂—CH═CH—CH₂— 104  iProp OH OiProp iProp H H H CH═C —CH₂— —CH₂—CH═CH—CH₂— 105  iProp OMe H H CN tBut H CH═C —CH₂— —CH₂—CH═CH—CH₂— 106  iProp OMe H H F tBut H CH═C S —CH₂—C(CH₃)═CH—CH₂— 107  iProp OMe H H Cl iProp H CH═C O —CH₂—C(CH₃)═CH—CH₂— 108  iProp OMe H tBut H H OMe CH═C NH —CH₂—C(CH₃)═CH—CH₂— 109  iProp NHMe OMe tBut H tBut H CH₂—N S —CH₂—CH═CH—CH₂— 110  iProp NHMe OMe tBut H CF₃ H CH₂—N —CH₂— —CH₂—CH═CH—CH₂— 111  iProp NHMe OMe CF₃ H tBut H CH₂—N S —CH₂—CH═CH—CH₂— 112  iProp NHMe H nProp CN tBut H CH₂—N NH —CH₂—C(CH₃)═CH—CH₂— 113  iProp NHMe H CF₃ CN iProp H CH₂—N S —CH₂—C(CH₃)═CH—CH₂— 114  iProp OH H Ph C═CH tBut H CH₂—N —CH₂— —CH₂—C(CH₃)═CH—CH₂— 115  iProp OH OMe tBut CN H H CH₂—N NH —CH₂—C(CH₃)═CH—CH₂— 116  iProp OH H tBut CN CF₃ OMe CH₂—N S —CH₂—CH═CH—CH₂— 117  iProp OH OMe nProp F tBut H CH═C —CH₂— —CH₂—CH═CH—CH₂— 118  iProp OMe H Ph CN tBut Me CH═C —CH₂— —CH₂—CH═CH—CH₂— 119  iProp OMe OMe tBut F H H CH═C S —CH₂—C(CH₃)═CH—CH₂— 120  iProp OMe H iProp H H OMe CH═C S —CH₂—C(CH₃)═CH—CH₂—

TABLE 5

Example No. R1 R2 R6 R8 R9 X—Y A¹ A² 121 CH₃ NH₂ tBut Ph H CH₂—N —CH₂— —(CH₂)₃— 122 CH₃ NH₂ tBut 2-Napht H CH₂—N S —CH₂—C(CH₃)═CH—CH₂— 123 CH₃ NH₂ tBut 1-Pyrrolyl H CH₂—N S —(CH₂)₃— 124 CH₃ NHMe tBut cHex H CH═C —CH₂— —(CH₂)₃— 125 CH₃ NH₂ tBut nHex H CH₂—N S —(CH₂)₅— 126 CH₃ NH₂ tBut H OMe CH₂—N —CH₂— —(CH₂)₃— 127 CH₃ NHMe iProp H OMe CH₂—N S —CH₂—C(CH₃)═CH—CH₂— 128 CH₃ NH₂ H CH₃ OMe CH═C NH —(CH₂)₃— 129 CH₃ NH₂ H iProp OMe CH₂—N O —CH₂—CH═CH—CH₂— 130 CH₃ NH₂ tBut tBut OMe CH₂—N —CH₂— —(CH₂)₃— 131 CH₃ NHMe tBut iProp OMe CH₂—N S —CH₂—C(CH₃)═CH—CH₂— 132 CH₃ NH₂ Ph tBut Cl CH₂—N S —(CH₂)₄— 133 CH₃ NH₂ 2-Napht tBut Me CH═C —CH₂— —(CH₂)₃— 134 CH₃ NH₂ tBut CF₃ OMe CH₂—N S —(CH₂)₃— 135 CH₃ NH₂ tBut H CH₃ CH₂—N S —(CH₂)₃— 136 iProp NH₂ tBut Ph H CH₂—N S —(CH₂)₃— 137 iProp NH₂ tBut 2-Napht H CH═C NH —(CH₂)₃— 138 iProp NH₂ tBut 1-Pyrrolyl H CH₂—N O —CH₂—C(CH₃)═CH—CH₂— 139 iProp NH₂ tBut cHex H CH₂—N —CH₂— —(CH₂)₃— 140 iProp OH tBut nHex H CH₂—N S —(CH₂)₄— 141 nProp OH tBut H OMe CH═C S —(CH₂)₄— 142 nProp OMe iProp H OMe CH₂—N —CH₂— —CH₂—CH═CH—CH₂— 143 nProp OMe H CH₃ OMe CH₂—N —CH₂— —(CH₂)₃— 144 nProp NCH₂Ph H iProp OMe CH₂—N S —CH₂—C(CH₃)═CH—CH₂— 145 iProp OH tBut tBut OMe CH₂—N —CH₂— —(CH₂)₄— 146 iProp OH tBut iProp OMe CH₂—N S —CH₂—CH═CH—CH₂— 147 iProp OMe Ph tBut Cl CH₂—N S —(CH₂)₅— 148 nProp OMe 2-Napht tBut Me CH═C —CH₂— —(CH₂)₃— 149 nProp NCH₂Ph tBut CF₃ OMe CH₂—N S —(CH₂)₄— 150 nProp NHMe tBut H CH₃ CH═C S —(CH₂)₃—

TABLE 6

Example No. R1 R2 R5 R7 R8 R9 X—Y A B 151 CH₃ NH₂ OMe H tBut H CH₂—N S —(CH₂)₃— 152 CH₃ OH OMe H CF₃ H CH₂—N S —(CH₂)₃— 153 iProp NHMe OMe H tBut H CH₂—N NH —CH₂—CH═CH—CH₂— 154 CH₃ NH₂ H CN tBut H CH═C —CH₂— —CH₂—C(CH₃)═CH—CH₂— 155 CH₃ NHMe H F tBut H CH₂—N S —(CH₂)₃— 156 cProp NH₂ Me Cl iProp H CH═C —CH₂— —(CH₂)₃— 157 CH₃ NHMe H H iProp OMe CH═C S —(CH₂)₃— 158 CH₃ NH₂ H H tBut OMe CH₂—N NH —CH₂—CH═CH—CH₂— 159 iProp NH₂ CN H CF₃ H CH₂—N S —(CH₂)₄— 160 OH NHMe H CN H OMe CH₂—N O —(CH₂)₃— 161 CH₃ OH H H tBu OEt CH═C S —CH₂—C(CH₃)═CH—CH₂— 162 Et NH₂ H CN tBut H CH₂—N —CH₂— —(CH₂)₃— 163 CH₃ NH₂ Me H iProp H CH₂—N S —(CH₂)₃— 164 iProp NH₂ OMe CN tBut H CH₂—N S —(CH₂)₄— 165 CH₃ NH₂ OMe Me tBut H CH₂—N S —(CH₂)₃— 166 CH₃ NHMe H CN tBut OMe CH₂—N NH —CH₂—CH═CH—CH₂— 167 CH₃ NH₂ Me H tBut OMe CH═C —CH₂— —CH₂—C(CH₃)═CH—CH₂— 168 iProp NH₂ H Cl CF₃ Me CH₂—N S —(CH₂)₅— 169 OH NHMe OMe CN tBut Me CH═C —CH₂— —(CH₂)₃— 170 CH₃ OH Me Me iProp Me CH═C S —(CH₂)₄— 171 CH₃ OH OMe H iProp H CH₂—N S —(CH₂)₃—

TABLE 7

Example No. R1 R2 R5 R6 R8 R9 X—Y A¹ A² 172 CH₃ NH₂ H tBut tBut H CH₂—N S —(CH₂)₃— 173 CH₃ OH H tBut Ph H CH₂—N S —(CH₂)₃— 174 iProp NHMe H tBut 1-Pyrrolyl H CH₂—N NH —CH₂—CH═CH—CH₂— 175 CH₃ NH₂ H nPropyl tBut H CH═C —CH₂— —CH₂—C(CH₃)═CH—CH₂— 176 CH₃ NHMe H CF₃ tBut H CH₂—N S —(CH₂)₃— 177 cProp NH₂ H 2-Napht tBut H CH═C —CH₂— —(CH₂)₃— 178 CH₃ NHMe OMe tBut H H CH═C S —(CH₂)₃— 179 CH₃ NH₂ OMe iProp H H CH₂—N NH —CH₂—CH═CH—CH₂— 180 iProp NH₂ OMe H CF₃ H CH₂—N S —(CH₂)₄— 181 OH NHMe H tBut H OMe CH₂—N O —(CH₂)₃— 182 CH₃ OH H iProp H Me CH═C S —CH₂—C(CH₃)═CH—CH₂— 183 Et NH₂ CN tBut H H CH₂—N —CH₂— —(CH₂)₃— 184 CH₃ NH₂ H H CF₃ Me CH₂—N S —(CH₂)₃— 185 OH NHMe OMe tBut iProp H CH₂—N S —(CH₂)₄— 186 CH₃ OH OMe CF₃ tBut H CH₂—N NH —CH₂—CH═CH—CH₂— 187 Et NH₂ Me tBut nProp H CH═C —CH₂— —CH₂—C(CH₃)═CH—CH₂— 188 CH₃ NH₂ Me tBut H OMe CH₂—N S —(CH₂)₅— 189 CH₃ NH₂ OMe tBut tBut OMe CH═C —CH₂— —(CH₂)₃— 190 iProp NH₂ Me CF₃ tBut OMe CH═C S —(CH₂)₄— 191 CH₃ OH H nProp tBut H CH₂—N S —(CH₂)₃—

TABLE 8

Example No. R1 R2 R6 R7 R8 R9 X—Y A¹ A² 192 CH₃ NH₂ tBut H tBut H CH₂—N S —(CH₂)₃— 193 CH₃ OH tBut CN H H CH₂—N S —(CH₂)₃— 194 iProp NHMe tBut H H OMe CH₂—N NH —CH₂—CH═CH—CH₂— 195 CH₃ NH₂ H CN tBu H CH═C —CH₂— —CH₂—C(CH₃)═CH—CH₂— 196 CH₃ NHMe CF₃ H tBut H CH₂—N S —(CH₂)₃— 197 cProp NH₂ nProp H iProp H CH═C —CH₂— —(CH₂)₃— 198 CH₃ NHMe H H iProp OMe CH═C S —(CH₂)₃— 199 CH₃ NH₂ tBut H tBut H CH₂—N NH —CH₂—CH═CH—CH₂— 200 iProp NH₂ tBut CN H H CH₂—N S —(CH₂)₄— 201 OH NHMe tBut H H OMe CH₂—N O —(CH₂)₃— 202 CH₃ OH H CN tBu H CH═C S —CH₂—C(CH₃)═CH—CH₂— 203 Et NH₂ CF₃ H tBut H CH₂—N —CH₂— —(CH₂)₃— 204 CH₃ NH₂ nProp H iProp H CH₂—N S —(CH₂)₃— 205 CH₃ NH₂ nProp CN tBut H CH₂—N S —(CH₂)₄— 206 CH₃ OH CF₃ CN iProp H CH₂—N S —(CH₂)₃— 207 iProp NHMe Ph C═CH tBut H CH₂—N NH —CH₂—CH═CH—CH₂— 208 CH₃ NH₂ tBut CN tBut H CH═C —CH₂— —CH₂—C(CH₃)═CH—CH₂— 209 CH₃ NHMe tBut H nProp OMe CH₂—N S —(CH₂)₃— 210 cProp NH₂ Ph H tBut OMe CH═C —CH₂— —(CH₂)₅— 211 CH₃ NHMe CF₃ H tBut OMe CH═C S —(CH₂)₃— 212 CH₃ NH₂ tBut F H Me CH₂—N NH —CH₂—CH═CH—CH₂— 213 iProp NH₂ nProp CN tBut Me CH₂—N S —CH₂—CH═CH—CH₂— 214 CH₃ OH nProp C═CH tBut OMe CH═C —CH₂— —CH₂—C(CH₃)═CH—CH₂— 215 iProp NHMe tBut CN H OMe CH₂—N S —(CH₂)₄— 216 CH₃ OH H H iProp OMe CH₂—N S —(CH₂)₃—

Examples of Pharmaceutical Forms

A) Tablets

Tablets of the following composition are compressed in a tabletting machine in a conventional manner:

40 mg of substance of Example 1

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg of Aerosil® (chemically pure silica in submicroscopically fine dispersion)

6.75 mg of potato starch (as 6% strength paste)

B) Sugar-coated Tablets

20 mg of substance of Example 4

60 mg of core composition

70 mg of sugar-coating composition

The core composition comprises 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition comprises 5 parts of sucrose, corn starch, 2 parts of calcium carbonate and 1 part talc. The sugar coated tablets produced in this way are subsequently provided with an enteric coating.

Biological Investigations—Receptor-binding Studies

1) D₃ Binding Assay

Cloned human D₃ receptor-expressing CCL 1.3 mouse fibroblasts obtained from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.

Cell Preparation

The D₃-expressing cells where grown in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U/ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, Md., USA). After 48h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization with medium was then carried out, and the cells were collected by centrifugation at 300×g. To lyze the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4, with 10% glycerol) and then incubated in a concentration of 10⁷ cells/ml of lysis buffer at 4° C. for 30 min. The cells were centrifuged at 200×g for 10 min and the pellet was stored in liquid nitrogen.

Binding Assays

For the D₃ receptor binding assay, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4, with 120 nM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA) in a concentration of about 10⁶ cells/250 μl of assay mixture and incubated at 30° C. with 0.1 nM ¹²⁵iodosulpiride in the presence and absence of test substance. The non-specific binding was determines using 10⁻⁶ M spiperone.

After 60 min, the free and the bound radioligand was separated by filtration through GF/B glasd fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway), and the filters were washed with ice-cold tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA ligand scintillation counter.

The K_(i) values were determined by non-linear regression analysis using the LIGAND program.

2) D₂ Binding Assay

Membrane Preparation

a) Nucleus Caudatus (Bovine)

Nucleus caudatus was removed from bovine brain and washed with ice-cold 0.32 M sucrose solution. After determination of the weight, the material was committed and homogenized in 5-10 volumes of sucrose solution using a Potter-Evehjem homogenizer (500 rpm). The homogenate was centrifuged at 3,000×g for 15 minutes (4° C.), and the resulting supernatant was subjected to another 15-minute centrifugation at 40,000×g. The residue was then washed twice, by resuspension and centrifugation, with 50 mM tris-HCl, pH 7.4. The membranes were were stored in liquid nitrogen until used.

b) Striatum (Rat)

Striati from Sprague-Dawley rats were washed in ice-cold 0.32 M sucrose solution. After determination of the weight, the parts of the brain were homogenized in 5-10 volumes of sucrose solution using a Potter-Elvehjem homogenizer (500 rpm). The homogenate was centrifuged at 40,000×g for 10 minutes (4° C.), and then the residue was washed several times, by resuspension and centrifugation, with 50 mM tris-HCl, 0.1 mM EDTA and 0.01% ascorbic acid (pH 7.4). The washed residue was resuspended in the abovementioned buffer and incubated at 37° C. for 20 minutes (to break down the endogenous dopamine). The membranes were then washed twice with buffer and portions were frozen in liquid nitrogen. The membrane preparation was stable for a maximum of one week.

Binding Assay

a) ³H-Spiperone (D_(2low))

Nucleus caudatus membranes were taken up in incubation buffer (mM: tris-HCl 50, NaCl 120, KCl 5, MgCl₂ 1, CaCl₂ 2, pH 7.4). Various mixtures, each of 1 ml, were prepared:

Total binding: 400 μg of membranes+0.2 nmol/l ³H-spiperone (Du Pont de Nemours, NET-565)

Non-specific binding: as mixtures for total binding+10 μM (+)-butaclamol.

Test substance: as mixtures for total binding+increasing concentrations of test substance.

After incubation at 25° C. for 60 minutes, the mixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (from Zinsser, Frankfurt), and the filters were wshed with ice-cold 50 mM tris-KCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by non-linear regression analysis using the LIGAND program or by conversion of the IC₅₀ values using the formula of Cheng and Prusoff.

b) ³H-ADTN (D_(2high))

Striatum membranes were taken up in incubation buffer (50 mM tris-HCl, pH 7.4, 1 mM MnCl₂ and 0.1% ascorbic acid).

Various mixtures, each of 1 ml, were prepared.

Total binding: 300 μg wet weight+1 nM ³H-ADTN (Du Pont de Nemours, customer synthesis)+100 nM SCH 23390 (occupation of D1 receptors).

Non-specific binding: as mixtures for total binding+50 nM spiperone.

Test substance: as mixtures for total binding+increasing concentrations of test substance.

After incubation at 25° C. for 60 minutes, the nmixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (from Zinsser, Frankfurt), and the filters were wshed with ice-cold 50 mM tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The evaluation took place as under a).

In these assays, the compounds according to the invention show very good affinities and high selectivities for the D₃ receptor. The results obtained for representative compounds are compiled in the following Table 9.

TABLE 9 Receptor binding D₃ D₂ Example ¹²⁵I-sulpiride ³H-spiperone Selectivity No. K_(i) [nM] K_(i) [mM] K_(i)D₂/K_(i)D₃ 10 4.5 219 49 15 8.8 517 58 24 1.8 120 67 41 8.1 1,500 185 42 13.4 2,450 182 37 1.7 300 176

For comparison, the compound of the formula

(U.S. Pat. No. 4,577,020; Example 3) was subjected to the above D₃ binding assay. A K_(i) of 4100 [nM] was found; ie. the compound-has virtually no affinity for the D₃ receptor. 

We claim:
 1. A triazole compound of formula I

wherein A is a straight-chain or branched C₁-C₁₈-alkylene group, or a straight chain or branched group consisting of 1 to 18 methylene members and one or two members selected from the group consisting of O, S, NR³, NR³CO, COO, OCO, C₃-C₆-cycloalkylene, a double bond and a triple bond, X is

R¹ is H, CO₂R³, NR³R⁴, OR⁴, C₃-C₆-cycloalkyl or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen; R² has the meanings indicated for R¹ or is CF₃, SR³, halogen or CN; R³ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl, phenyl or halogen; R⁴ has the meanings indicated for R³ or is COR³ or CO₂R³; Ar is an optionally fused phenyl ring selected from the group consisting of phenyl, naphthalene, dihydronaphthalene, tetrahydronaphthalene, quinoline, dihydroquinoline, tetrahydroquinoline, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole and benzotriazole, and which optionally fused phenyl ring is unsubstituted or carries from one to four substituents selected from the group consisting of: OR⁴, C₁-C₈-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, CO₂R³, NO₂, SO₂R³, SO₃R³, NR³R⁴, SO₂NR³R⁴, SR³, CF₃, CHF₂, C₃-C₆-cycloalkyl, phenyl, naphthalene, pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole and thiadiazole, wherein each of the cyclic substituents is unsubstituted or substituted by C₁-C₈-alkyl, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃, or a salt thereof with a physiologically tolerated acid.
 2. The compound of formula I defined in claim 1, wherein the optionally fused phenyl ring is selected from the group consisting of phenyl, naphthalene, dihydronaphthalene, tetrahydronaphthalene, quinoline, dihydroquinoline, tetrahydroquinoline, indole, dihydroindole and benzothiazole.
 3. The compound of formula I defined in claim 1, wherein the optionally fused phenyl ring is unsubstituted or carries from one to four substituents selected from the group consisting of: OR⁴, C₁-C₈-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, CO₂R³, NO₂, SO₂R³, SO₃R³, NR³R⁴, SO₂NR³R⁴, SR³, CF₃, CHF₂, C₃-C₆-cycloalkyl, phenyl, naphthalene, pyrrolidine, piperidine, morpholine, pyrrole, thiophene and imidazole.
 4. The compound of formula I defined in claim 1, wherein the optionally fused phenyl ring is selected from the group consisting of phenyl, naphthalene, dihydronaphthalene, tetrahydronaphthalene, quinoline, dihydroquinoline, tetrahydroquinoline, indole, dihydroindole and benzothiazole, and which optionally fused phenyl ring is unsubstituted or carries from one to four substituents selected from the group consisting of: OR⁴, C₁-C₈-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, CO₂R³, NO₂, SO₂R³, SO₃R³, NR³R⁴, SO₂NR³R⁴, SR³, CF₃, CHF₂, C₃-C₆-cycloalkyl, phenyl, naphthalene, pyrrolidine, piperidine, morpholine, pyrrole, thiophene and imidazole, wherein each of the cyclic substituents is unsubstituted or substituted by C₁-C₈-alkyl, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃.
 5. The compound of formula I defined in claim 1, wherein the optionally fused phenyl ring Ar is selected from the group consisting of phenyl, naphthalene, dihydronaphthalene and tetrahydronaphthalene, and which optionally fused phenyl ring is unsubstituted or carries from one to four substituents selected from the group consisting of: OR⁴, C₁-C₈-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, CO₂R³, NO₂, SO₂R³, SO₃R³, NR³R⁴, SO₂NR³R⁴, SR³, CF₃, CHF₂, C₃-C₆-cycloalkyl, phenyl, naphthalene, pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole and thiadiazole, wherein each of the cyclic substituents is unsubstituted or substituted by C₁-C₈-alkyl, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃.
 6. The compound of formula I defined in claim 1, wherein Ar is a phenyl ring which is unsubstituted or substituted by from one to four substituents selected from the group consisting of: OR⁴, C₁-C₈-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, CO₂R³, NO₂, SO₂R³, SO₃R³, NR³R⁴, SO₂NR³R⁴, SR³, CF₃, CHF₂, C₃-C₆-cycloalkyl, phenyl, naphthalene, pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole and thiadiazole, wherein each of the cyclic substituents is unsubstituted or substituted by C₁-C₈-alkyl, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃.
 7. The compound of formula I defined in claim 1 wherein R¹ is H, CO₂R³, NR³R⁴, OR⁴ or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen; R³ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen; and wherein the optionally fused phenyl ring is unsubstituted or carries one or two substituents selected from the group consisting of: OR⁴, C₁-C₈-alkyl, halogen, CN, CO₂R³, NO₂, SO₂R³, SO₃R³, NR³R⁴, SO₂NR³R⁴, SR³, CF₃, CHF₂, C₃-C₆-cycloalkyl, phenyl, naphthalene, pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole and thiadiazole, wherein each of the cyclic substituents is unsubstituted or substituted by C₁-C₈-alkyl, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃.
 8. The compound of formula I defined in claim 5 wherein R¹ is H, CO₂R³, NR³R⁴, OR⁴ or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen; R³ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen; and wherein the optionally fused phenyl ring is unsubstituted or carries one or two substituents selected from the group consisting of: OR⁴, C₁-C₈-alkyl, halogen, CN, CO₂R³, NO₂, SO₂R³, SO₃R³, NR³R⁴, SO₂NR³R⁴, SR³, CF₃, CHF₂, C₃-C₆-cycloalkyl, phenyl, naphthalene, pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole and thiadiazole, wherein each of the cyclic substituents is unsubstituted or substituted by C₁-C₈-alkyl, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃.
 9. The compound of the formula I defined in claim 1 wherein A is C₁-C₁₀-alkylene or a group consisting of 1 to 10 methylene members and one or two radicals selected from the group consisting of O, S, NR_(3,) cyclohexylene, a double bond and a triple bond.
 10. The compound of the formula I defined in claim 5 wherein A is C₁-C₁₀-alkylene or a group consisting of 1 to 10 methylene members and one or two radicals selected from the group consisting of O, S, NR³, cyclohexylene, a double bond and a triple bond.
 11. The compound of the formula I defined in claim 5 wherein R¹ is H or OR⁴, where R⁴ is H, C₃-C₆-cycloalkyl or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen; R² is H, C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or NR³R⁴, where R³ and R⁴ are, independently of one another, H, phenyl-C₁-C₈-alkyl or C₁-C₈-alkyl, or OR⁴ where R⁴ is H or C₁-C₈-alkyl, or CF₃; and Ar is phenyl which is unsubstituted or carries one, two, three or four substituents selected from the group consisting of C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or OR⁴ where R⁴ is H, C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or CHF₂, CF₃, CN, halogen, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, phenyl, naphthalene, pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole and thiadiazole.
 12. The compound of the formula I defined in claim 5 wherein R¹ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen; R² is H, C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or NR³R⁴ where R³ and R⁴ are, independently of one another, H or C₁-C₈-alkyl, or OR⁴ where R⁴ is H or C₁-C₈-alkyl, or CF₃; A is C₁-C₁₀-alkylene or a group consisting of 1 to 10 methylene members and one member selected from the group consisting of oxygen, sulfur and NR³; Ar is phenyl which is unsubstituted or carries from one to four substituents selected from the group consisting of: CN, SR³, halogen, C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or phenyl, naphthalene, OR⁴, NO₂, NR³R⁴, CHF₂ and CF₃.
 13. The compound of the formula I defined in claim 12 wherein A is SC₃-C₁₀-alkylene, OC₃-C₁₀-alkylene or NR³-C₃-C₁₀-alkylene, where R³ is H or C₁-C₈-alkyl; R¹ is H or C₁-C₈-alkyl; Ar is phenyl which is unsubstituted or carries from one to four substituents selected from the group consisting of C₁-C₈-alkyl, OC₁-C₈-alkyl, CHF₂, CF₃ and CN.
 14. The compound of the formula I defined in claim 13 wherein the phenyl ring Ar is substituted by one or two substituents which are located in position 3 and position 5, with one substituent being CF₃, CHF₂ or C₁-C₈-alkyl and the other substituent being H or C₁-C₈-alkyl.
 15. The compound of the formula I defined in claim 1 wherein R¹ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, R² is H, NR³R⁴ or OR⁴ where R³ and R⁴ are, independently of one another, H, C₁-C₈-alkyl or phenyl-C₁-C₈-alkyl; A is C₁-C₁₀-alkylene or is a group consisting of 1 to 10 methylene members and one or two members selected from the group consisting of O, S, NR³ where R³ is H or C₁-C₈-alkyl, a double bond and a triple bond.
 16. The compound of the formula I defined in claim 5 wherein R¹ is H or C₁-C₈-alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, R² is H, NR³R⁴ or OR⁴ where R³ and R⁴ are, independently of one another, H, C₁-C₈-alkyl or phenyl-C₁-C₈-alkyl; A is C₁-C₁₀-alkylene or is a group consisting of 1 to 10 methylene members and one or two members selected from the group consisting of O, S, NR³ where R³ is H or C₁-C₈-alkyl, a double bond and a triple bond.
 17. A pharmaceutical composition containing the compound of formula I defined in claim 13 and a conventional pharmaceutical aid.
 18. A method for treating a disorder which responds to dopamine D₃ receptor ligands, which comprises administering an effective amount of the compound of formula I defined in claim 1 to a person requiring such treatment.
 19. The method of claim 18, wherein the disorder which responds to dopamine D₃ receptor ligands is schizophrenia, depression, a neurosis or a psychosis. 